Effect of cyclosporine on mycophenolic acid area under the concentration-time curve in pediatric kidney transplant recipients

Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF) , shows substantial interindividual and intraindividual variability. It was recently shown that in vitro calcineurin inhibitors alter the bioavailabil ity of MPA by dose-dependent inhibition of MPA glucuronidation. The authors retrospectively analyzed full 10-point profiles for both MPA and cyclospor ine (CyA) in 23 pediatric patients receiving MMF and cyclosporine microemul sion (Neoral; Novartis Pharmaceuticals Canada; Dorval, Quebec, Canada). Myc ophenolic acid was measured using a commercially available EMIT (Novartis P harmaceuticals, Canada) assay. As the majority of patients were treated wit h low doses of cyclosporine after Lidding MMF, the area under the concentra tion-time curve (AUC) for cyclosporine showed a wide scatter ranging from 2 96 to 6400 ng x h/mL. The mean cyclosporine dose was 100 +/- 76 mg/m(2) per day (range: 28 to 331). There was no correlation between MPA AUC and MPA d ose, and there was substantial interindividual variation. However, there wa s a significant negative correlation between dose-normalized MPA AUC and cy closporine AUC (r(2) = 0.23, p<0.0220). When dividing the MPA profiles into two groups (11 and 12 patients) with a CyA AUC less than or greater than 1 600 ng x h/mL, there was a significantly higher 8-hour concentration in the patients with the lower CyA AUC, secondary to a higher second peak. The da ta demonstrate that the cyclosporine AUC is a determining factor for the MP A AUC and that MPA dose should be reduced when cyclosporine dose is reduced to achieve the same MPA AUC. The significantly higher peak in the group wi th a lower CyA profile supports the concept of a dose-dependent cyclosporin e-induced inhibition of MPA glucuronidation.